Synthesis of the C4-C17 fragment of saliniketals a and b

Article abstract of DOI:10.1002/ejoc.201300012

A highly stereoselective synthesis of the C4-C17 fragment of saliniketals A and B was completed. The key steps in this synthesis included a syn-aldol reaction mediated by a boron enolate and a double diastereodifferentiating aldol reaction mediated by a titanium enolate. Moreover, a substrate-controlled Grignard reaction, an intramolecular Wacker-type cyclization and a Seyferth-Gilbert homologation provided the C4-C17 fragment of saliniketals A and B in 16 steps and with a 7 % overall yield. Copyright

Full text of DOI:10.1002/ejoc.201300012

Job/Unit: O30012
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Date: 18-03-13 12:18:14
Pages: 11
FULL PAPER
DOI: 10.1002/ejoc.201300012
Synthesis of the C4–C17 Fragment of Saliniketals A and B
Luiz C. Dias*[a] and Carla C. Perez[a]
Keywords: Natural products / Asymmetric synthesis / Aldol reactions / Polyketides
A highly stereoselective synthesis of the C4–C17 fragment of
saliniketals A and B was completed. The key steps in this
synthesis included a syn-aldol reaction mediated by a boron
enolate and a double diastereodifferentiating aldol reaction
mediated by a titanium enolate. Moreover, a substrate-con-
trolled Grignard reaction, an intramolecular Wacker-type cy-
clization and a Seyferth–Gilbert homologation provided the
C4–C17 fragment of saliniketals A and B in 16 steps and with
a 7% overall yield.
ODC have attracted great interest from the scientific com-
munity. To date, two total syntheses of saliniketal B,[3,4] one
total synthesis of saliniketal A,[3] and a formal synthesis of
both polyketides have been completed.[5] In 2010, a study
regarding their biosynthesis was reported by Moore and co-
workers.[6]
We were inspired by the synthetic challenge and the
structural complexity presented by these bicyclic polyket-
ides, saliniketals A (1) and B (2). In this paper, we report
the synthesis of the C4–C17 fragment of 1 and 2, which
contains the nine stereogenic centers and the 2,8-dioxabicy-
clo[3.2.1]octane core of these natural products. As fragment
3 was an important intermediate in the synthesis of 1 and
2 by Paterson and co-workers, this approach constitutes a
formal total synthesis of saliniketals A (1) and B (2).[3]
Introduction
The marine-derived saliniketals A (1) and B (2) (Fig-
ure 1) were isolated from strains of the marine actinobac-
teria Salinispora arenicola by Fenical and co-workers in
2007.[1] These polyketides (1 and 2) are important targets
in cancer prevention as they are inhibitors of ornithine de-
carboxylase (ODC), with IC50 values of 1.95Ϯ0.37 and
7.83Ϯ1.2 μg/mL, respectively.[1,2] The planar structures and
relative stereochemistries of these polyketides were deter-
mined using 2D NMR spectroscopy experiments, and the
absolute stereochemistries were assigned using the modified
Mosher method.[1] A total synthesis of these compounds
was completed by the Paterson group in 2008,[3] and this
confirmed the absolute stereochemistry proposed by Fen-
ical and co-workers.
Results and Discussion
Our proposal for the total synthesis of saliniketals A (1)
and B (2) includes a Stille coupling of a common advanced
intermediate 3.[3] The retrosynthesis of C4–C17 fragment 3
began with a disconnection of the triple bond leading to
aldehyde 4; we proposed that this reaction could be
achieved in the forward sense by a Seyferth–Gilbert homol-
ogation.[7] We hypothesized that aldehyde 4 could be con-
structed from 5 by an intramolecular Wacker-type cycliza-
tion followed by removal of the benzyl protecting group
and oxidation of the primary alcohol functionality.[3,5] We
recognized that intermediate 5 could be prepared from a
Grignard reaction between 6 and aldehyde 7.[5,8] Aldehyde
7 could be obtained from an aldol reaction between the
titanium enolate of 8 and (S)-9.[9] We hypothesized that
fragment 8 could be obtained from a syn-selective aldol re-
action of (S)-11 and (R)-10 (Scheme 1).[10]
Figure 1. Saliniketals A (1) and B (2) and fragment C4–C17 (3).
Since the isolation of saliniketals A and B in 2007, their
interesting molecular architectures and potent inhibition of
[a] Institute of Chemistry, State University of Campinas,
UNICAMP,
C.P. 6154, Campinas, SP, Brazil
Our approach began with the preparation of fragment 8
(C8–C13). The aldol reaction of the boron enolate gener-
ated from (S)-11 with aldehyde (R)-10[11] provided aldol
product 12 in 75% yield (over two steps, i.e., preparation
Fax: +55-19-3521-3023
E-mail: ldias@iqm.unicamp.br
Homepage: http://lqos.iqm.unicamp.br/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300012.
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FULL PAPER
Scheme 1. Retrosynthetic analysis for the C4–C17 fragment of saliniketals A and B.
Scheme 2. Preparation of ethyl ketone 8.
of the aldehyde and aldol coupling) and greater than 95:5 13 with the corresponding Grignard reagent led to the for-
diastereoselectivity (Scheme 2).[10,12,13] Transamidation of mation of ethyl ketone 8 in 51% yield over three steps.
12 with MeOMeNH·HCl and Me3Al in THF at 0 °C was
followed by silylation with TBSOTf (TBS = tert-butyldi- to
Next, aldehyde (S)-9[11] and ethyl ketone 8 were subjected
a
double diastereodifferentiating aldol reaction
methylsilyl) and 2,6-lutidine in CH2Cl2 to provide amide 13 (Scheme 3) using Ti(iPrO)Cl3 as a Lewis acid in the pres-
in 73% yield over two steps. Treatment of Weinreb amide ence of DIPEA (diisopropylethylamine).[9,14] Aldol product
2
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Synthesis of the C4-C17 Fragment of Saliniketals A and B
Scheme 3. Double diastereodifferentiating aldol reaction leading to 14.
14 was obtained in 60% yield and 80:20 diastereoselectivity anti-H6,H7 relationship. Because the C6 stereocenter is
for the two-step sequence (Scheme 3). We also isolated known to have an R configuration, as in the starting mate-
product 15, with a free secondary hydroxy group at C11, in rial, it was concluded that the major diastereomer (i.e., 14),
15% yield. When we tested the reaction using an excess of was the compound with the desired stereochemistry for the
DIPEA (1.8 equiv.) at –78 °C, we avoided the deprotection synthesis of saliniketals A and B, as shown in Figure 2.
at C11 (Scheme 3), and aldol adduct 14 was obtained in
The preferential formation of diastereomer 14 can be ex-
89% yield and 90:10 diastereoselectivity.
plained by a chelated cyclic transition state leading to the
The assignment of the relative stereochemistry of the anti-Felkin adduct as the major product (Scheme 4).[17]
major diastereomer (i.e., 14) was carried out based on the
rules of Murata and co-workers. This method is based on
the conformational analysis of acyclic systems, and relies on
2,3
proton–proton (3JH,H) and carbon–proton
J
coupling
C,H
constants.[15,1]
This study was performed after all of the H and 13C
NMR signals were assigned based on the DEPT-135 spec-
trum and the correlations observed in HSQC, HMBC,
COSY, and NOESY experiments. A mixture of [D5]pyridine
and [D4]methanol (1:1) was used as the NMR solvent to
1
minimize intramolecular hydrogen bonding.[15]
2,3
After obtaining the
J
coupling constants using the
C,H
3
HSQC-TOCSY-IPAP[16] technique and the JH,H coupling
1
constants by analyzing the H NMR spectra (see Support-
ing Information for more details), it was possible to use the
empirical rules of Murata and co-workers[15] for the assign-
ment of the relative stereochemistry of the major aldol
product.
For the major diastereomer (i.e., 14), the coupling con-
3
3
2
stants JH7,H8 = 4.5 Hz, JC3,H7 = 4.1 Hz and JC8,H7
=
Scheme 4. Proposed transition state for the formation of 14.
The next step in the synthesis was the 1,3-anti stereo-
–3.5 Hz indicated that the two rotamers, I and II, were the
predominant species in solution with respect to the C7–C8
bond (Figure 2). The data suggested that H8 and 7-OH selective reduction of aldol product 14 using NaBH(OAc)3
have gauche and anti interactions, similar to the pair of rot- generated in situ by adding NaBH4 to glacial acetic acid
amers shown in Figure 2. These rotamers indicated a syn- (92% yield, ds Ͼ 95:5).[18] Compound 16 was treated with
3
H7,H8 relationship. The observed values of JH6,H7
=
=
2,2-dimethoxypropane and a catalytic amount of CSA for
24 h to provide the corresponding acetonide (i.e., 17) in
3
2
7.2 Hz (medium), JC4,H7 = 2.0 Hz (small) and JC7,H6
–4.7 Hz (medium) indicated that the rotamers III and IV 98% yield (Scheme 5). NMR analysis of acetonide 17 also
predominate for the C6–C7 bond, (Figure 2), suggesting an confirmed the 1,3-anti stereochemical relationship between
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L. C. Dias, C. C. Perez
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Figure 2. Proof of the relative stereochemistry of major diastereomer 14.
Scheme 5. Preparation of aldehyde 7.
C7 and C9.[19] Removal of the PMB (para-methoxybenzyl)
group in the presence of DDQ (2,3-dichloro-5,6-dicyano-
1,4-benzoquinone) and a buffer (pH = 7) followed by oxi-
dation of the primary alcohol functionality under Swern
conditions provided aldehyde 7, which was used in the next
step without further purification (Scheme 5). The strategy
behind using the Grignard reaction was based on the Fel-
kin-controlled addition of 6 to aldehyde 7.[5,20] The Grig-
nard reagent was slowly added to a solution of 7 in THF
at –78 °C. Product 5 was obtained in 97% yield and 95:5
diastereoselectivity (Scheme 6).
Scheme 6. Preparation of compound 5.
4
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Synthesis of the C4-C17 Fragment of Saliniketals A and B
To confirm the relative stereochemistry of product 5 and
Next, removal of the benzyl protecting group in the pres-
continue the synthesis, the secondary TBS group was re- ence of Raney nickel provided primary alcohol 21, which
moved using TBAF (tetrabutylammonium fluoride) in was also synthesized and characterized by Paterson and co-
THF, and this was followed by a Wacker-type intramolecu- workers in their synthesis of saliniketals A and B. This al-
lar cyclization reaction using catalytic amounts of PdCl2 lowed for a comparison of our data with their reported
together with CuII as a co-oxidant.[3] This sequence pro- data; the 1H and 13C NMR chemical shifts of our synthetic
vided spiroketal 20 in 83% yield and with high regio- and compound perfectly matched the values reported for this
stereoselectivity (Scheme 7). At this point, we confirmed compound by the Paterson group (see Table 1 and Support-
that the spectral and optical rotation data of advanced in- ing Information).[3,5] The optical rotation for compound 21
termediate 20 agreed with the data reported for this com- obtained in our work was +6.0 (c = 0.78, CHCl3), whereas
pound by Paterson and co-workers in their synthesis of sali- the optical rotation for the same compound obtained by
1
niketals A and B.[3] The H and 13C NMR chemical shifts Paterson and co-workers was +6.2 (c = 0.81, CHCl3).
and the observed optical rotation, i.e., [α]2D0 = –8.3 (c = 0.30,
Oxidation of alcohol 21 in the presence of TPAP (tetra-
CHCl3) matched the reported values for this compound, propylammonium perruthenate),[22] followed by Seyferth–
i.e., [α]2D0 = –8.6 (c = 0.33, CHCl3).[3,21]
Gilbert homologation using freshly prepared Bestmann–
Scheme 7. Preparation of spiroketal 21.
Table 1. Comparison between the 1H and 13C NMR spectroscopic data for compound 3 obtained in this work with the same compound
described by Paterson and co-workers.[3]
.
Position
1H, compound 3[a]
1H, compound 3 (ref.[3] [b]
)
13C, compound 3[a] 13C, compound 3 (ref.[3] [b]
)
4
5
6
2.04 (1 H, d J = 2.3 Hz)
2.04 (d, 1 H, J = 2.3 Hz)
–
68.4
87.2
27.1
68.4
87.2
27.1
–
2.53 (1 H, ddq, J = 13.8, 6.8, 2.3 Hz) 2.53 (1 H, ddq, J = 13.7, 6.7,
2.2 Hz)
7
8
9
3.65 (dd, 1 H, J = 10.3, 3.7 Hz)
1.75–1.91 (m, 1 H)
3.30 (1 H, dd, J = 9.0, 6.5 Hz)
1.64–1.71 (m, 1 H)
3.73 (dd, 1 H, J = 10.8, 2.0 Hz)
1.93–2.00 (m, 1 H)
4.20 (dd, 1 H, J = 6.2, 3.9 Hz)
1.75–1.91 (m, 2 H)
1.75–1.91 (m, 2 H)
–
3.65 (dd, 1 H, J = 10.5, 3.7 Hz)
1.75–1.91 (m, 1 H)
3.30 (dd, 1 H, J = 8.9, 6.5 Hz)
1.64–1.71 (m, 1 H)
3.73 (dd, 1 H, J = 10.8, 2.1 Hz)
1.93–2.00 (m, 1 H)
4.20 (dd, 1 H, J = 6.0, 3.8 Hz)
1.75–1.91 (m, 2 H)
1.75–1.91 (m, 2 H)
–
1.42 (s, 3 H)
–
1.13 (d, 3 H, J = 6.9 Hz)
0.88 (d, 6 H, J = 6.9 Hz)
0.88 (d, 6 H, J = 6.9 Hz)
0.69 (d, 3 H, J = 7.0 Hz)
1.34 (s, 3 H)
72.9
36.0
80.3
38.8
72.8
33.8
74.5
24.2
34.2
104.9
25.6
100.8
16.6
12.4
7.8
72.8
36.0
80.2
38.8
72.7
33.8
74.5
24.2
34.2
104.8
25.6
100.8
16.6
12.4
7.8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1.42 (s, 3 H)
–
1.13 (d, 3 H, J = 7.0 Hz)
0.88 (d, 6 H, J = 6.8 Hz)
0.88 (d, 6 H, J = 6.8 Hz)
0.68 (d, 3 H, J = 7.0 Hz)
1.34 (s, 3 H)
12.5
23.4
24.0
12.5
23.4
24.0
1.36 (s, 3 H)
1.36 (s, 3 H)
[a] 1H and proton-decoupled 13C NMR spectra were recorded in CDCl3 at 400 MHz (1H) and 100 MHz (13C). [b] In the literature report,
1
the H and proton-decoupled 13C NMR spectra were recorded in CDCl3 at 500 MHz (1H) and 125 MHz (13C).
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Other reagents were used without pretreatment. Compounds were
purified by flash column chromatography using silica gel (230–
400 mesh) as the stationary phase. The mobile phase used is speci-
fied for each experimental procedure. Thin-layer chromatography
(TLC) on silica gel 60 and GF (5–40 μm thickness) plates was used
for monitoring the progress of reactions. TLC plates were visual-
ized using UV light and then stained with phosphomolybdic acid
and heat. The maximum absorbance wavelengths (max) of infrared
spectra are presented in wavenumbers (cm–1). The angles of devia-
tion of the polarized light (α) are described as follows: (c [g/
100 mL], solvent). High-resolution mass spectrometry (HRMS)
was performed using electrospray ionization (ESI). 1H and proton-
decoupled 13C NMR spectra were recorded in C6D6, CDCl3, [D4]-
methanol, or [D5]pyridine at 250 MHz (1H) and 62.9 MHz (13C);
400 MHz (1H) and 100 MHz (13C); or 500 MHz (1H) and 125 MHz
(13C). The chemical shifts (δ) are reported in ppm using the solvent
peak as an internal standard ([D4]methanol at δ = 3.30 ppm, C6D6
at δ = 7.16 ppm, and CDCl3 at δ = 7.26 ppm for 1H NMR spectra,
and [D4]methanol at δ = 49.0 ppm, C6D6 at δ = 128.0 ppm, and
CDCl3 at δ = 77.0 ppm for 13C NMR spectra). Data are reported as
follows: multiplicity (s = singlet, br. s = broad singlet, d = doublet, t
= triplet, q = quartet, quint = quintuplet, sext = sextet, dd = doub-
let of doublets, dt = doublet of triplets, dq = doublet of quartets,
ddd = doublet of doublet of doublets, td = triplet of doublets, tt =
triplet of triplets, qd = quartet of doublets, or m = multiplet), cou-
pling constant(s) in Hz, integration.
Scheme 8. Preparation of alkyne 3.
Ohira reagent, provided alkyne 3 in 82% yield over two
steps (Scheme 8).[7]
These satisfactory results allowed us to complete the
preparation of C4–C17 fragment 3, which contains all nine
stereogenic centers present in the structures of saliniketals
A (1) and B (2). This fragment also contains the 2,8-dioxa-
bicyclo[3.2.1]octane core and a triple bond, which is amena-
ble to further functionalization.
(S)-4-Benzyl-3-{(2S,3R,4R)-3-hydroxy-5-[(4methoxybenzyl)oxy]-
2,4-dimethylpentanoyl}oxazolidin-2-one (12): Freshly distilled
nBu2BOTf (1.9 g, 6.9 mmol, 1.74 mL, d = 1.089 g/mL) was slowly
added to a solution of chiral auxiliary (S)-11 (1.50 g, 6.3 mmol) in
CH2Cl2 (4 mL) at –10 °C under an argon atmosphere. Then,
DIPEA (1.4 g, 10.7 mmol, 1.8 mL) was added dropwise. The tem-
perature was reduced to –78 °C, and a cooled solution (ice bath)
of aldehyde (R)-10 (1.7 g, 8.2 mmol) in CH2Cl2 (2 mL) was added
Conclusions
In conclusion, we have achieved the formal total synthe-
sis of the bicyclic polyketides saliniketals A (1) and B (2).[3] dropwise. The reaction mixture was maintained at –78 °C for
30 min and then at –10 °C for 2 h. Then, phosphate buffer (11 mL)
and methanol (31 mL) were added, followed by the slow addition
of a 2:1 mixture of MeOH (28 mL) and H2O2 (25% aq.; 14 mL),
with stirring, over 1 h at –5 °C. The solvents were removed under
vacuum, and the crude mixture was extracted with ethyl ether (3ϫ
30 mL). The organic phase was washed with NaHCO3 (saturated
aq.; 90 mL) and NaCl (saturated aq.; 90 mL), and dried with anhy-
drous Na2SO4, and the solvents were evaporated under vacuum.
The crude reaction product was purified by flash column
chromatography (silica gel, hexane/CH2Cl2/EtOAc, 75:20:5) to give
2.1 g of compound 12 (75%, dr = 95:5) as a pale yellow oil. Rf =
The synthesized C4–C17 fragment contains all of the nine
contiguous stereogenic centers present in the saliniketals, a
triple bond and the core 2,8-dioxabicyclo[3.2.1]octane. Our
synthetic route used 16 steps and provided the desired prod-
uct in 7% overall yield for the longest linear route.
Experimental Section
General Remarks: All reactions, unless otherwise specified, were
performed under an atmosphere of argon. Dichloromethane, tolu-
ene, triethylamine (Et3N), diisopropylethylamine (DIPEA), tita-
nium tetrachloride, tin tetrachloride, acetonitrile (CH3CN), and di-
methyl sulfoxide (DMSO) were treated with calcium hydride and
distilled prior to use. Tetrahydrofuran (THF) and ethyl ether (Et2O)
were treated with calcium hydride, distilled, and treated with so-
dium and benzophenone prior to use. Acetic acid (AcOH) was dis-
tilled in the presence of acetic anhydride and KMnO4. Oxalyl
chloride was distilled immediately prior to use. Titanium tetraisop-
ropoxide Ti(iPrO)4 was distilled under vacuum (0.8 Torr, 60 °C)
and used immediately. Camphorsulfonic acid (CSA) was recrys-
tallized from ethyl acetate and then dried under vacuum. Raney
nickel (2 g) was heated at 50 °C for 4 h in aqueous NaOH (6 m,
250 mL) and then cooled to room temperature; next, the superna-
tant was decanted, and the solid was washed repeatedly with dis-
tilled water until the pH reached 7.0. The solid was then washed
with absolute ethanol and used immediately. Molecular sieves (4 Å)
were activated at 160–200 °C under vacuum (0.8 Torr) for 12 h.
0.21 (20% EtOAc in hexane). [α]2D0 = +21.0 (c = 1.1, CHCl3).[23] 1
H
NMR (500 MHz, CDCl3): δ = 0.96 (d, J = 6.5 Hz, 3 H), 1.27 (d,
J = 7.0 Hz, 3 H), 1.95–2.09 (m, 1 H), 2.79 (dd, J = 10.0, 13.5 Hz,
1 H), 3.32 (dd, J = 3.0, 13.5 Hz, 1 H), 3.54 (dd, J = 7.0, 9.5 Hz, 1
H), 3.58 (dd, J = 4.5, 9.5 Hz, 1 H), 3.80 (s, 3 H), 3.88 (dd, J = 3.3,
8.3 Hz, 1 H), 3.96 (dq, J = 3.3, 7.0 Hz, 1 H), 4.17 (m, 2 H), 4.45
(s, 2 H), 4.68 (m, 1 H), 6.88 (d, J = 8.5 Hz, 2 H), 7.26 (m, 7 H)
ppm. 13C NMR (62.9 MHz, CDCl3): δ = 9.6, 13.4, 35.8, 37.5, 40.5,
54.8, 55.4, 65.9, 73.0, 74.4, 75.2, 113.6, 127.1, 128.2, 128.8, 129.1,
129.7, 135.1, 153.0, 159.1, 176.0 ppm. IR (film): ν = 3481, 3010,
˜
2968, 2935, 1780, 1699, 1514, 1386, 1245, 1211, 757 cm–1. HRMS
(ESI-TOF): calcd. for C25H32NO6 442.2230; found 442.2208.
(2S,2R,4R)-3-[(tert-Butyldimethylsilyl)oxy]-N-methoxy-5-[(4-meth-
oxybenzyl)oxy]-N,2,4-trimethylpentanamide (13)
Step 1: Al(CH3)3 (2.0 m in toluene; 25.5 mL, 51 mmol) was added
slowly to a suspension of N,O-dimethylhydroxyamine (5.2 g,
6
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Synthesis of the C4-C17 Fragment of Saliniketals A and B
53 mmol) in THF (38 mL). The reaction mixture was maintained
at 0 °C for 30 min and then at room temperature for 90 min. Next,
the reaction temperature was adjusted to –20 °C, and a solution of
aldol product 12 (5.8 g, 13.2 mmol) in THF (26.4 mL) was added
by cannula. The temperature was increased to 0 °C, and the reac-
tion mixture was stirred for 90 min. Then, the reaction mixture was
transferred by cannula to a flask containing HCl (0.5 m; 153 mL,
77 mmol) and CH2Cl2 (153 mL), and the resulting mixture was
stirred at 0 °C for 90 min. The aqueous phase was extracted with
CH2Cl2 (2 ϫ 100 mL), and the organic phase was washed with
NaCl (saturated aq.; 300 mL) and dried with anhydrous Na2SO4.
The product was obtained as a yellow oil and was used in the next
step without purification.
one (14): Freshly distilled Ti(iPrO)4 (83 μL, 0.3 mmol) was added
to a solution of TiCl4 (92 μL, 0.8 mmol) in CH2Cl2 (1.0 mL) at
0 °C under an argon atmosphere. The yellow mixture was stirred
for 10 min at 0 °C, and for 10 min at room temperature. Further
CH2Cl2 (1.0 mL) was added, and the resulting colorless solution
was added over 10–15 min to a solution of ethyl ketone 8 (1 mmol)
in CH2Cl2 (2 mL) at –78 °C under an argon atmosphere, and this
was followed by the addition of DIPEA (0.2 mL, 1.1 mmol). The
resulting dark red solution was stirred for 1.5 h at –78 °C. After
this time, aldehyde 9 (1.5 equiv.) was added, and the mixture was
stirred for 30 min at –20 °C. After the addition of NH4Cl (saturated
aq.; 5 mL) under vigorous stirring at room temperature, the mix-
ture was diluted with ethyl ether (10 mL) and washed with H2O
(10 mL), NaHCO3 (saturated aq.; 10 mL), and NaCl (saturated
aq.; 10 mL). The aqueous phases were extracted with ethyl ether
(60 mL), and the combined organic phases were dried with anhy-
drous MgSO4. The crude mixture was subjected to flash column
chromatography (silica gel and hexane/EtOAc/CH2Cl2, 75:5:20) to
give 14 [35.2 mg (60%) over two steps, i.e., preparation of the alde-
hyde and the aldol reaction; diastereoselectivity (14/15) = 80:20] as
a colorless oil, together with a by-product (15%) resulting from
deprotection of the secondary alcohol. If all other parameters were
kept constant but 1.8 equiv. DIPEA was used and the reaction tem-
perature was lowered to –78 °C, the yield improved to 89 %
(52.2 mg) and a 90:10 diastereoselectivity in favor of the desired
product (i.e., 14). Rf = 0.5 (20% EtOAc in hexane). [α]2D0 = +13.0
Step 2: CH2Cl2 (34 mL) was added to a flask containing the Wein-
reb amide (8.2 g, 25 mmol), and the resulting solution was cooled
to 0 °C. Then, 2,6-lutidine (19.4 mL, 166 mmol) was added, fol-
lowed by TBSOTf (15.1 mL, 70 mmol). The reaction mixture was
stirred at 0 °C for 10 min, and then at 25 °C for 1.5 h. After this
time, ethyl ether (30 mL) and cold NaHSO4 (1 n; 100 mL) were
added. The reaction mixture was extracted with ethyl ether (3ϫ
100 mL), and the organic extracts were washed with distilled water
(100 mL), NaHCO3 (saturated aq.; 100 mL), and NaCl (saturated
aq.; 100 mL). The combined organic extracts were dried with anhy-
drous Na2SO4 and concentrated under reduced pressure. The crude
reaction product was purified by flash column chromatography (sil-
ica gel, hexane/EtOAc at a gradient concentration of 20–40 %
EtOAc), providing 8.2 g of product 13 as a pale yellow oil in 73%
1
(c = 0.5, CHCl3). H NMR (400 MHz, [D4]methanol:[D5]pyridine
yield over two steps. Rf = 0.36 (20% EtOAc in hexane). [α]2D0
=
1:1): δ = –0.04 (s, 3 H), –0.01 (s, 3 H), 0.79 (s, 9 H), 0.81 (d, J =
7.1 Hz, 3 H), 0.89 (d, J = 6.8 Hz, 3 H), 1.04 (d, J = 7.1 Hz, 3 H),
1.11 (d, J = 7.1 Hz, 3 H), 1.79 (m, 1 H), 1.90 (m, 1 H), 3.04 (dd, J
= 4.5, 7.1 Hz, 1 H), 3.14 (dd, J = 5.4, 7.1 Hz, 1 H), 3.20 (dd, J =
6.6, 9.1 Hz, 1 H), 3.42 (dd, J = 6.4, 9.2 Hz, 1 H), 3.50 (dd, J = 6.3,
9.1 Hz, 1 H), 3.60 (s, 3 H), 3.70 (dd, J = 5.4, 9.2 Hz, 1 H), 4.00
(dd, J = 4.5, 7.2 Hz, 1 H), 4.20 (t, J = 4.5 Hz, 1 H), 4.33 (br. s, 2
H), 4.38 (d, J = 4.0 Hz, 2 H), 6.84 (d, J = 8.0 Hz, 2 H), 7.20–7.28
(m, 7 H) ppm. 13C NMR (100 MHz, [D4]methanol:[D5]pyridine
1:1): δ = –3.8, –3.3, 11.1, 14.1, 15.6, 15.8, 19.2, 26.8, 38.1, 39.9,
48.3, 48.9, 55.6, 72.9, 73.6, 73.8, 74.0, 74.1, 74.7, 114.7, 124.8,
128.7, 129.2, 130.3, 131.9, 137.3, 139.9, 160.4, 217.4 ppm. IR (film):
+8.0 (c = 1.02, CHCl3).[24] 1H NMR (250 MHz, C6D6): δ = 0.10
(s, 3 H), 0.14 (s, 3 H), 1.02 (s, 9 H), 1.18 (d, J = 7.0 Hz, 3 H), 1.34
(d, J = 7.0 Hz, 3 H), 2.27–2.18 (m, 1 H), 2.86 (s, 3 H), 3.08 (br. s,
3 H), 3.30 (dd, J = 5.3, 9.0 Hz, 2 H), 3.31 (s, 3 H), 3.68 (dd, J =
8.3, 2.8 Hz, 1 H), 4.31 (dd, J = 7.5, 12.0 Hz, 1 H), 4.38 (s, 2 H),
6.78 (d, J = 8.8 Hz, 2 H), 7.24 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR
(62.9 MHz, CDCl3): δ = –3.9, 15.0, 15.4, 18.3, 26.1, 32.1, 38.8, 39.2,
55.2, 61.2, 71.8, 72.6, 76.0, 113.6, 129.2, 130.8, 159.0, 176.7 ppm.
IR (film): ν = 3018, 2958, 2935, 2858, 1649, 1512, 1249, 1215,
˜
757 cm–1. HRMS (ESI-TOF): calcd. for C23H42NO5Si 440.2832;
found 440.2805.
ν = 3475, 2956, 2931, 2881, 2856, 1697, 1614, 1514, 1461, 1454,
˜
(4S,5R,6R)-5-[(tert-Butyldimethylsilyl)oxy]-7-(4-methoxybenzyl)-
oxy-4,6-dimethylheptan-3-one (8): EtMgBr (2.0 m in THF; 12 mL,
24 mmol) was added dropwise to a solution of 13 (3.3 g, 8.0 mmol)
in dry THF (130 mL) at 0 °C. The reaction was complete after
1.5 h, and it was quenched by the careful addition of NH4Cl (satu-
rated aq.; 100 mL). The phases were separated, and the aqueous
phase was extracted with ethyl ether (3ϫ 200 mL). The combined
organic phases were dried with Na2SO4 (500 mL) and concentrated
under reduced pressure. Purification by flash column chromatog-
raphy (silica gel and hexane/EtOAc, 80:20) gave product 8 (2.1 g,
70%) as a pale yellow oil. Rf = 0.8 (20% EtOAc in hexane). [α]2D0
= +11.0 (c = 2.2, CHCl3). 1H NMR (250 MHz, C6D6): δ = 0.07 (s,
3 H), 0.05 (s, 3 H), 0.95–1.01 (m, 6 H), 0.97 (s, 9 H), 1.07 (d, J =
7.5 Hz, 3 H), 1.96–2.29 (m, 3 H), 2.60–2.71 (m, 1 H), 3.23 (dd, J
= 7.5, 10.0 Hz, 1 H), 3.31 (s, 3 H), 3.47 (dd, J = 5.0, 7.5 Hz, 1 H),
4.19–4.23 (m, 1 H), 4.28 (d, J = 12.5 Hz, 1 H), 4.34 (d, J = 12.5 Hz,
1 H), 6.80 (d, J = 8.9 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H) ppm. 13C
NMR (62.9 MHz, C6D6): δ = –4.1, –4.9, 7.8, 14.7, 18.6, 26.3, 34.8,
39.5, 49.4, 54.7, 72.1, 73.0, 74.7, 114.0, 129.4, 129.8, 159.7,
1362, 1301, 1250, 1092, 1039, 999, 833 cm–1. HRMS (ESI-TOF):
calcd. for C34H54O6SiNa 609.3588; found 609.3587.
(2S,3S,4R,5R,6R,7R,8R)-1-(Benzyloxy)-7-[(tert-butyldimethylsilyl)-
oxy]-9-[(4-methoxybenzyl)oxy]-2,4,6,8-tetramethylnonane-3,5-diol
(16): NaBH4 (32.3 mg, 0.89 mmol) was added to acetic acid
(0.6 mL) at 0 °C. After the evolution of gas ceased (approximately
10 min), the reaction was stirred at room temperature for 1 h, fol-
lowed by the addition of a solution of aldol product 14 (54 mg,
0.09 mmol) in acetic acid (0.3 mL). After 40 min, the solvent was
removed under reduced pressure, and NaHCO3 (saturated aq.;
2.5 mL) was added with caution to the residue. The aqueous phase
was extracted with dichloromethane (3ϫ 3 mL), and the combined
organic extracts were washed with NaCl (saturated aq.; 12 mL),
dried with anhydrous Na2SO4, and concentrated in vacuo. The resi-
due was purified by flash chromatography (silica gel and hexanes/
EtOAc, 90:10) to give the desired product (49.9 mg, 92%, Ͼ95:5
diasteroselectivity) as a colorless oil. Rf = 0.4 (20% EtOAc in hex-
1
ane). [α]2D0 = +3.0 (c = 0.41, CHCl3). H NMR (250 MHz, C6D6):
212.1 ppm. IR (film): ν = 3016, 2958, 2935, 2856, 1708, 1612, 1514,
˜
δ = 0.17 (s, 3 H), 0.30 (s, 3 H), 0.56 (d, J = 7.1 Hz, 3 H), 0.87 (d,
J = 6.8 Hz, 3 H), 1.03 (s, 9 H), 1.13 (d, J = 7.3 Hz, 3 H), 1.24 (d,
J = 7.3 Hz, 3 H), 1.73–1.81 (m, 1 H), 1.86–1.97 (m, 1 H), 2.12–
2.18 (m, 2 H), 3.27–3.31 (m, 2 H), 3.31 (s, 3 H), 3.39 (dd, J = 7.3,
8.7 Hz, 1 H), 3.61–3.71 (m, 2 H), 3.94 (d, J = 9.6 Hz, 1 H), 4.04
1461, 1361, 1249, 1095, 1039, 837, 757 cm–1. HRMS (ESI-TOF):
calcd. for C23H40O4SiNa 431.2594; found 431.2614.
(2S,3S,4R,6S,7R,8R)-1-(Benzyloxy)-7-[(tert-butyldimethylsilyl)oxy]-
3-hydroxy-9-[(4-methoxybenzyloxyl)oxy]-2,4,6,8-tetramethylnona-5-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O30012
/KAP1
Date: 18-03-13 12:18:14
Pages: 11
L. C. Dias, C. C. Perez
= 7.3 Hz, 2 H), 9.70 (d, J = 2.2 Hz, 1 H) ppm. 13C NMR
FULL PAPER
(d, J = 7.6 Hz, 1 H), 4.16 (br. s, 2 H), 4.38 (s, 1 H), 4.41 (s, 1 H),
4.45 (m, 1 H), 6.82 (d, J = 8.7 Hz, 2 H), 7.04–7.23 (m, 5 H), 7.27 (125 MHz, C6D6): δ = –4.2, –3.7, 10.4, 11.0, 12.9, 13.4, 18.7, 24.8,
(d, J = 8.7 Hz, 2 H) ppm. 13C NMR (62.9 MHz, C6D6): δ = –4.2,
–3.8, 11.1, 11.5, 13.0, 15.2, 18.7, 26.5, 34.2, 36.4, 39.1, 39.9, 54.8,
72.0, 73.3, 74.3, 76.1, 76.2, 78.0, 114.1, 127.8, 127.9, 128.3, 128.7,
25.7, 26.2, 34.3, 36.2, 42.3, 53.1, 69.8, 72.4, 72.8, 73.4, 77.3, 100.6,
127.3, 127.9, 138.5, 202.8 ppm. IR (film): ν = 2983, 2932, 2857,
˜
1724, 1379, 1265, 1223, 740 cm–1. HRMS (ESI-TOF): calcd. for
C28H47O5Si 491.3193; found 491.3232.
129.4, 138.3, 159.6 ppm. IR (film): ν = 3460, 2930, 2856, 1651,
˜
1643, 1633, 1614, 1506, 1464, 1265, 1094, 1036, 739 cm–1. HRMS
(ESI-TOF): calcd. for C34H57O6Si 589.3925; found 589.3918.
(5S,6R,7R,8R)-8-{(4R,5R,6S)-6-[(S)-1-(Benzyloxy)propan-2-yl]-
2,2,5-triemethyl-1,3-dioxan-4-yl}-7-[(tert-butyldimethylsilyl)oxy]-
(2R,3R,4R)-4-{(4R,5R,6S)-6-[(S)-1-(Benzyloxy)propan-2-yl]-2,2,5- 6-methylnon-1-en-5-ol (5)
trimethyl-1,3-dioxan-4-yl}-3-[(tert-butyldimethylsilyl)oxy]-2-
Preparation of the Grignard Reagent: A solution of 4-bromo-1-but-
methylpentan-1-ol (17)
ene (18; 7.2 g, 53.0 mmol) in THF (25 mL) was added dropwise to
a suspension of pre-activated magnesium metal (2.1 g, 87.5 mmol)
in THF (5 mL) in a two-necked flask coupled to an addition funnel
and a reflux condenser. The reaction mixture was stirred at room
temperature for 4.5 h.
Step 1: A solution of CSA (5 mg) in 2,2-dimethoxypropane
(6.3 mL) was added to a flask containing diol 16 (96 mg,
0.16 mmol) at 25 °C under an argon atmosphere with magnetic stir-
ring. Magnetic stirring was maintained for 18 h at room tempera-
ture, and then NaHCO3 (saturated aq.; 10 mL) and ethyl ether
(10 mL) were added. The organic phase was separated and dried
with anhydrous Na2SO4. The product was obtained as a colorless
oil, which was used in the next step without purification.
Addition of the Grignard Reagent to the Aldehyde: Grignard reagent
solution (0.16 mL) was added slowly over approximately 1 h to a
solution of aldehyde 7 (50 mg, 0.10 mmol) in THF (1 mL) at
–78 °C. After the addition was complete, the reaction mixture was
brought to room temperature, stirred for 1 h, and then quenched
Step 2: This compound (83.6 mg, 0.13 mmol) was dissolved in a
mixture of CH2Cl2 and pH 7.0 buffer (18:1; 2.1 mL) at 0 °C, and with NH4Cl (saturated aq.; 1.5 mL). The organic phase was dried
DDQ (45.2 mg, 0.20 mmol) was added. The resulting mixture was
stirred at room temperature for 30 min. Distilled H2O (3 mL) was
added, the mixture was filtered, and the supernatant was collected.
The aqueous phase was extracted with CH2Cl2 (3ϫ 5 mL). The
combined organic extracts were dried with anhydrous Na2SO4 and
concentrated on a rotary evaporator. The crude mixture was puri-
fied by flash column chromatography (silica gel and hexanes/
with anhydrous Na2SO4 and concentrated under vacuum. The re-
sulting residue was purified by flash column chromatography (silica
gel and hexanes/EtOAc, 85:15) to give the product (53.8 mg, 97%,
dr Ͼ 95:5) as a yellow oil. Rf = 0.75 (20 % EtOAc in hexane).
1
[α]2D0 = +12.0 (c = 2.0, CH2Cl2). H NMR (250 MHz, C6D6): δ =
0.15 (s, 6 H), 0.89 (d, J = 6.6 Hz, 3 H), 0.94 (d, J = 6.8 Hz, 3 H),
1.00 (s, 9 H), 1.03 (d, J = 7.3 Hz, 3 H), 1.09 (d, J = 7.1 Hz, 3 H),
EtOAc, 80:20) to give the product (48.6 mg, 70%) as a pale yellow 1.33 (s, 3 H), 1.38 (s, 3 H), 1.41–2.37 (m, 8 H), 2.85 (d, J = 2.2 Hz,
oil. Rf = 0.6 (20% EtOAc in hexane). [α]2D0 = +8.0 (c = 0.8, CH2Cl2).
1 H), 3.26 (dd, J = 6.5 Hz, 1 H), 3.54 (m, 2 H), 3.78 (dd, J = 3.8,
1H NMR (250 MHz, C6D6): δ = 0.15 (s, 6 H), 0.84 (d, J = 6.9 Hz, 10.7 Hz, 1 H), 4.01–4.06 (m, 1 H), 4.17 (m, 1 H), 4.33 (d, J =
3 H), 0.89 (d, J = 6.4 Hz, 3 H), 0.94 (d, J = 6.9 Hz, 3 H), 0.96 (d,
J = 6.8 Hz, 3 H), 1.02 (s, 9 H), 1.32 (s, 3 H), 1.37 (s, 3 H), 1.72–
2.05 (m, 4 H), 2.64 (br. s, 1 H), 3.23 (dd, J = 6.6, 9.8 Hz, 1 H),
3.48–3.61 (m, 4 H), 3.78 (dd, J = 3.9, 10.8 Hz, 1 H), 4.26 (d, J =
4.4 Hz, 1 H), 4.35 (s, 2 H), 7.09–7.21 (m, 3 H), 7.30 (d, J = 7.1 Hz,
2 H) ppm. 13C NMR (62.9 MHz, C6D6): δ = –4.3, –4.1, 11.3, 12.8,
13.4, 14.3, 18.6, 24.2, 25.4, 26.2, 34.1, 36.6, 39.1, 43.2, 65.3, 70.1,
12.6 Hz, 1 H), 4.28 (d, J = 12.6 Hz, 1 H), 4.95 (d, J = 10.1 Hz, 2
H), 5.10 (dd, J = 1.7, 17.1 Hz, 2 H), 5.79–5.95 (m, 1 H), 7.06–7.21
(m, 3 H), 7.31 (d, J = 7.3 Hz, 2 H) ppm. 13C NMR (62.9 MHz,
C6D6): δ = –4.4, –3.5, 10.3, 11.7, 12.8, 13.4, 18.6, 24.2, 25.5, 26.3,
31.0, 34.2, 34.9, 36.6, 42.1, 45.4, 70.1, 71.1, 72.4, 73.4, 77.1, 78.7,
100.8, 114.7, 127.6, 127.7, 128.3, 128.5, 139.2, 139.5 ppm. IR (film):
ν = 3421, 2978, 1641, 1454, 1379, 1265, 1085, 1047, 739 cm–1
.
˜
72.3, 72.5, 73.4, 79.0, 100.9, 127.3, 127.9, 138.4 ppm. IR (film): ν HRMS (ESI-TOF): calcd. for C33H59O5Si 563.4132; found
˜
= 3487, 2960, 2934, 2855, 1698, 1684, 1601, 1579, 1511, 1262, 1161,
1028 cm–1. HRMS (ESI-TOF): calcd. for C28H49O5Si 493.3349;
found 493.3396.
563.4127.
(2S,3R,4R,5S)-2-{(4S,5R,6S)-6-[(S)-1-(Benzyloxy)propan-2-yl]-
2,2,5-trimethyl-1,3-dioxan-4-yl}-4-methylnon-8-ene-3,5-diol (19):
TBAF (1 m in THF; 0.06 mL, 0.06 mmol) was added to a solution
of compound 5 (17 mg, 0.03 mmol) in THF (0.2 mL) at room tem-
perature. The reaction mixture was stirred for 16 h, then it was
concentrated under reduced pressure, and the residue was purified
by flash column chromatography (silica gel and hexanes/EtOAc,
80:20) to give the product (11.0 mg, 85%) as a colorless oil. Rf =
(2S,3S,4R)-4-{(4R,5R,6S)-6-[(S)-1-(Benzyloxy)propan-2-yl]-2,2,5-
trimethyl-1,3-dioxan-4-yl}-3-[(tert-butyldimethylsilyl)oxy]-2-
methylpentanal (7): DMSO (0.02 mL, 0.29 mmol) was added to a
solution of oxalyl chloride (0.02 mL, 0.21 mmol) in CH2Cl2
(1.0 mL) at –78 °C. After 30 min, alcohol 17 (39 mg, 0.08 mmol)
dissolved in CH2Cl2 (0.3 mL) was added. After stirring for 30 min
at –78 °C, triethylamine (0.07 mL, 0.48 mmol) was added, and the
resulting mixture was stirred for 1.5 h at –78 °C. After this time,
the reaction was quenched by adding NH4Cl (saturated aq.; 2 mL).
The phases were separated, and the aqueous phase was extracted
with ethyl ether (3ϫ 2 mL). The combined organic phases were
dried with anhydrous Na2SO4, filtered, and concentrated on a ro-
tary evaporator. The crude reaction product was used in the follow-
ing step without further purification. Rf = 0.7 (20% EtOAc in hex-
1
0.25 (20% EtOAc in hexane). [α]2D0 = +5.0 (c = 1.15, CH2Cl2). H
NMR (500 MHz, C6D6): δ = 0.71 (d, J = 7.1 Hz, 3 H), 0.76 (d, J
= 6.6 Hz, 3 H), 0.91 (d, J = 6.8 Hz, 3 H), 1.07 (d, J = 7.1 Hz, 3
H), 1.17 (s, 3 H), 1.22 (s, 3 H), 1.44–1.47 (m, 1 H), 1.57–1.59 (m,
1 H), 1.74–1.96 (m, 4 H), 2.20–2.21 (m, 1 H), 2.42–2.48 (m, 1 H),
2.80 (br. s, 1 H), 3.32 (dd, J = 2.9, 7.8 Hz, 1 H), 3.44–3.49 (m, 2
H), 3.53 (s, 1 H), 4.05 (d, J = 8.1 Hz, 1 H), 4.19 (d, J = 9.5 Hz, 1
H), 4.31 (d, J = 12.2 Hz, 1 H), 4.33 (d, J = 12.2 Hz, 1 H), 4.99
ane). +23.0 (c = 1.5, CH2Cl2). 1H NMR (250 MHz, C6D6): δ = (ddt, J = 1.2, 2.2, 10.2 Hz, 1 H), 5.10 (ddd, J = 1.8, 3.9, 17.1 Hz,
0.08 (s, 3 H), 0.13 (s, 3 H), 0.85 (d, J = 7.1 Hz, 3 H), 0.89 (d, J = 1 H), 5.83–5.91 (m, 1 H), 7.07–7.10 (m, 1 H), 7.16–7.18 (m, 2 H),
6.8 Hz, 3 H), 0.93–0.96 (m, 6 H), 0.97 (s, 9 H), 1.30 (s, 3 H), 1.38
7.27 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR (125 MHz, C6D6): δ =
(s, 3 H), 1.64–1.73 (m, 2 H), 1.81–1.91 (m, 1 H), 2.43–2.45 (m, 1 11.5, 11.97, 11.98, 13.5, 23.3, 24.8, 26.0, 25.9, 31.5, 33.0, 34.3, 35.8,
H), 3.24 (dd, J = 6.2, 9.0 Hz, 1 H), 3.55 (m, 2 H), 3.76 (dd, J = 37.3, 40.6, 70.6, 72.3, 72.8, 73.4, 81.3, 101.2, 114.6, 127.6, 127.7,
3.6, 10.7 Hz, 1 H), 4.40 (br. s, 2 H), 7.10–7.22 (m, 3 H), 7.32 (d, J 127.9, 128.3, 128.5, 139.3 ppm. IR (film): ν = 3485, 2978, 2935,
˜
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30012
/KAP1
Date: 18-03-13 12:18:14
Pages: 11
Synthesis of the C4-C17 Fragment of Saliniketals A and B
1454, 1381, 1265, 1381, 1265, 1223, 739 cm–1. HRMS (ESI-TOF):
calcd. for C26H41O5 433.2954; found 433.2965.
ture. K2CO3 (2.9 mg, 0.002 mmol) was added, and the mixture was
stirred at room temperature for 18 h. The reaction was quenched
with NH4Cl (saturated aq.; 0.5 mL). The aqueous phase was ex-
tracted with EtOAc (3ϫ 1 mL), and the combined organic extracts
were concentrated under reduced pressure. The product was puri-
fied by flash column chromatography (silica gel and hexanes/
EtOAc, 90:10) to give the desired product (2.4 mg, 82%) as a color-
less oil. Rf = 0.5 (20% EtOAc in hexane). [α]2D0 = –8.9 (c = 0.30,
CHCl3); ref.[3] –8.8 (c = 0.28, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 0.68 (d, J = 7.0 Hz, 3 H), 0.88 (d, J = 6.8 Hz, 6 H),
1.13 (d, J = 7.0 Hz, 3 H), 1.34 (s, 3 H), 1.36 (s, 3 H), 1.42 (s, 3 H),
1.64–1.71 (m, 1 H), 1.75–1.91 (m, 5 H), 1.93–2.00 (m, 1 H), 2.04
(d, J = 2.3 Hz, 1 H), 2.53 (ddq, J = 13.8, 6.8, 2.3 Hz, 1 H), 3.30
(dd, J = 9.0, 6.5 Hz, 1 H), 3.65 (dd, J = 10.3, 3.7 Hz, 1 H), 3.73
(dd, J = 10.8, 2.0 Hz, 1 H), 4.20 (dd, J = 6.2, 3.9 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 7.8, 12.4, 12.5, 16.6, 23.4, 24.0,
24.2, 25.6, 27.1, 33.8, 34.2, 36.0, 38.8, 68.4, 72.8, 72.9, 74.5, 80.3,
(1S,3R,4R,5S)-3-((R)-1-{(4R,5R,6S)-6-[(S)-1-(Benzyloxy)propano-
2-yl]-2,2,5-trimethyl-1,3-dioxan-4-yl}ethyl)-1,4-dimethyl-2,8-dioxa-
bicyclo[3.2.1]octane (20): CuCl2 (4.8 mg, 0.04 mmol) and PdCl2
(6.3 mg, 0.04 mmol) were added to a solution of 19 (80.5 mg,
0.18 mmol) in THF (1.8 mL) at 0 °C. The reaction was purged
three times with oxygen and stirred vigorously for 24 h at 0 °C.
The reaction was quenched with diethyl ether (2.0 mL) and filtered
through a “plug” containing Na2SO4 and SiO2 (1:1). The crude
extract was concentrated on a rotary evaporator and the residue
was purified by flash column chromatography (silica gel and hex-
anes/EtOAc, 80:20) to give the desired product (65.9 mg, 83%) as
a colorless oil. Rf = 0.6 (20% EtOAc in hexane). [α]2D0 = –8.3 (c =
0.3, CHCl3); ref.[3] –8.6 (c = 0.33, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 0.66 (d, J = 7.1 Hz, 3 H), 0.87 (d, J = 7.1 Hz, 3 H),
0.89 (d, J = 7.3 Hz, 3 H), 0.94 (d, J = 6.6 Hz, 3 H), 1.25 (s, 3 H),
1.27 (s, 3 H), 1.41 (s, 3 H), 1.69–1.73 (m, 1 H), 1.72–1.91 (m, 6 H),
1.92–1.98 (m, 1 H), 3.27 (dd, J = 9.3, 6.6 Hz, 1 H), 3.43 (dd, J =
8.8, 6.3 Hz, 1 H), 3.57 (dd, J = 8.8, 3.2 Hz, 1 H), 3.63 (dd, J =
10.7, 3.7 Hz, 1 H), 3.72 (dd, J = 10.5, 1.9 Hz, 1 H), 4.19 (dd, J =
6.1, 3.4 Hz, 1 H), 4.46 (d, J = 11.7 Hz, 1 H), 4.48 (d, J = 11.7 Hz,
1 H), 7.31–7.32 (m, 5 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
8.0, 12.6, 12.9, 13.4, 23.6, 24.1, 24.3, 25.8, 33.8, 33.9, 34.3, 36.3,
38.9, 70.3, 72.8, 72.9, 73.3, 74.9, 80.4, 100.4, 104.9, 127.4, 127.6,
87.2, 100.8, 104.9 ppm. IR (film): ν = 3266, 2956, 2922, 2850, 2333,
˜
1739, 1462, 1299, 1183, 1030 cm–1.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra, and IR and HRMS spectra for the
prepared compounds are available.
Acknowledgments
128.3, 139.1 ppm. IR (film): ν = 2982, 2935, 2879, 1462, 1379, 1265,
˜
The authors are grateful to the Fundo de Apoio ao Ensino e à
Pesquisa-Unicamp (FAEP-UNICAMP), to the Fundação de Am-
paro à Pesquisa do Estado de São Paulo (FAPESP), Conselho Na-
cional de Desenvolvimento Científico e Tecnológico (CNPq) and
to the Instituto Nacional de Ciência e Técnologia de Fármacos e
Medicamentos (INCT-INOFAR) (Proc. CNPq 573.564/2008-6) for
financial support.
1227, 1022, 739 cm–1.
(S)-2-((4S,5R,6R)-6-{(R)-1-[(1S,3R,4R,5S)-1,4-Dimethyl-2,8-di-
oxabicyclo[3.2.1]octan-3-yl]ethyl}-2,2,5-trimethyl-1,3-dioxan-4-yl)-
propan-1-ol (21): Catalytic amounts of Raney Ni were added to a
solution of benzyl ether 20 (10 mg, 0.023 mmol) in absolute ethanol
(0.5 mL). The reaction was purged with H2 and was left stirring at
room temperature for 7 d. The mixture was filtered through a plug
of Celite, and the product was purified by flash column chromatog-
raphy (silica gel and hexanes/EtOAc, 70:30) to give the product
(62 %) as a colorless oil, along with recovered starting material
(3.0 mg, 30%). Rf = 0.3 (30% EtOAc in hexane). [α]2D0 = +6.0 (c =
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1
0.78, CHCl3); ref.[3] +6.2 (c = 0.81, CHCl3). H NMR (500 MHz,
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CDCl3): δ = 0.69 (d, J = 7.1 Hz, 3 H), 0.77 (d, J = 6.8 Hz, 3 H),
0.90 (d, J = 7.1 Hz, 3 H), 0.94 (d, J = 6.8 Hz, 3 H), 1.32 (s, 3 H),
1.39 (s, 3 H), 1.44 (s, 3 H), 1.67–2.01 (m, 8 H), 3.34 (m, 1 H), 3.57
(m, 1 H), 3.61 (m, 1 H), 3.68 (dd, J = 10.5, 3.9 Hz, 1 H), 3.75 (dd,
J = 10.7, 1.9 Hz, 1 H), 4.22 (dd, J = 6.5, 3.7 Hz, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 7.9, 12.5, 12.6, 12.9, 23.4, 24.2, 26.0,
33.7, 34.2, 34.8, 36.4, 38.9, 69.4, 72.9, 74.6, 76.3, 80.2, 100.5,
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˜
1163, 1021, 983, 891 cm–1.
(1S,3R,4R,5S)-3-((R)-1-{(4R,5R,6S)-6-[(S)-But-3-yn-2-yl]-2,2,5-
trimethyl-1,3-dioxan-4-yl}ethyl)-1,4-dimethyl-2,8-dioxabicyclo-
[3.2.1]octane (3)
Preparation of the Aldehyde: Alcohol 21 (3 mg, 0.08 mmol) was dis-
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was added, and the reaction was stirred for 15 min. The suspension
was filtered through a small plug of silica, and the solvent was
removed under vacuum. The residue was used in the next step with-
out further purification.
Preparation of the Alkyne: Aldehyde 4 (3 mg, 0.008 mmol) and
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0.016 mmol) were dissolved in MeOH (0.5 mL) at room tempera-
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O30012
/KAP1
Date: 18-03-13 12:18:14
Pages: 11
L. C. Dias, C. C. Perez
FULL PAPER
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After contacting Prof. Ian Paterson and Mina Razzak, we con-
firmed that there was a typographical error in their publication
(ref.[3]) and that 13.4 ppm is the correct chemical shift for C19.
Another error concerns the assignment of the protons at posi-
tion 25 as a dd; these protons should be assigned as d,
4.46 ppm and d, 4.48 ppm.
[20]
[21]
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Received: January 5, 2013
Published Online: ᭿
10
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30012
/KAP1
Date: 18-03-13 12:18:14
Pages: 11
Synthesis of the C4-C17 Fragment of Saliniketals A and B
Natural Product Synthesis
The synthesis of the C4–C17 fragment of
saliniketals A and B was achieved. The syn-
thesized compound contains all of the nine
contiguous stereogenic centers present in
the saliniketals, a triple bond, and the 2,8-
dioxabicyclo[3.2.1]octane core present in
these natural products.
L. C. Dias,* C. C. Perez ................. 1–11
Synthesis of the C4–C17 Fragment of Sali-
niketals A and B
Keywords: Natural products / Asymmetric
synthesis / Aldol reactions / Polyketides
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11